Toll-like receptor 4 signaling pathway mediates proinflammatory immune response to cobalt-alloy particles

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• 作者：Pushya A. Potnis ; ^{pushya.potnis@fda.hhs.gov} ; Debargh K. Dutta ; Steven C. Wood
• 关键词：Metal-on-metal hips ; Co-alloy particles ; TLR4 signaling ; Cytokines ; Periprosthetic osteolysis
• 刊名：Cellular Immunology
• 出版年：2013
• 出版时间：March, 2013
• 年：2013
• 卷：282
• 期：1
• 页码：53-65
• 全文大小：1811 K

文摘

Metal orthopedic implant debris-induced osteolysis of hip bone is a major problem in patients with prosthetic-hips. Although macrophages are the principal targets for implant-wear debris, the receptor(s) and mechanisms underlying these responses are not fully elucidated. We examined whether the TLR4 pathway mediates immune response to metal-on-metal (MoM) implant-generated wear particles. Human monocytes (THP-1) were exposed to Co-alloy particles at increasing particle:cell ratio for 24 h. Challenge with particles caused up-regulation of IL-1¦Â, TNF-¦Á and IL-8, and mediated degradation of cytosolic I-¦ÊB and nuclear translocation of NF-¦ÊB. Blocking antibodies against TLR4 or gene silencing of MyD88 and IRAK-1 prevented particle-induced I-¦ÊB/NF-¦ÊB activation response and markedly inhibited IL-8 release. Particle-mediated IL-8 response was not observed in TLR4-negative HEK293T cells; whereas transfection-based TLR4-overexpression in HEK293T enabled particle-sensitivity, as observed by I-¦ÊB degradation and IL-8 expression in response to particles. Results demonstrate that Co-alloy particles trigger immune response via the TLR4-MyD88-dependent signaling pathway.